Posts in Review Paper
Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer: Implications for Oncogene-Driven Lung Cancer

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, commonly defined by genetic alterations in oncogenic drivers. Targeted therapies have transformed the management of oncogene-driven lung cancers, with targeted agents now approved in the United States for 7 distinct molecular alterations. Nonetheless, acquired resistance remains an ongoing challenge, underscoring the need for alternative therapeutic approaches. Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) axis have emerged as important therapies in the management of advanced NSCLC, but the role of these agents in patients with oncogenic driver mutations remains unclear. Here, we focus on epidermal growth factor receptor-mutant and anaplastic lymphoma kinase-rearranged NSCLC as paradigms to explore the role of immune checkpoint inhibitors in oncogene-driven NSCLC. We provide an overview of the clinical data examining programmed death ligand 1 (PD-L1) inhibitor monotherapy, PD-(L)1 inhibitors, and tyrosine kinase inhibitor combinations, as well as combinations of PD-(L)1 inhibitors and chemotherapy. READ ARTICLE

The Cancer Journal DOI: 10.1097/PPO.0000000000000491

Authors: Gavralidis A, Gainor JF.

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Food–Drug Interactions with Fruit Juices

Fruit juices contain a large number of phytochemicals that, in combination with certain drugs, can cause food–drug interactions that can be clinically significant and lead to adverse events. The mechanisms behind such interactions are in most cases related to phytochemical interference with the activity of cytochrome P450 metabolizing enzymes (CYPs) or drug transporters. Moreover, alterations in their activity can have a clinical relevance if systemic exposure to the drug is decreased or increased, meaning that the pharmacological drug effects are suboptimal, or the drug will cause toxicity. In general, the common pharmacokinetic parameters found to be altered in food–drug interactions regarding fruit juices are the area under the concentration–time curve, bioavailability, and maximum plasma concentration. In most cases, the results from the drug interaction studies with fruit juices provide only limited information due to the small number of subjects, which are also healthy volunteers. Moreover, drug interactions with fruit juices are challenging to predict due to the unknown amounts of the specific phytochemicals responsible for the interaction, as well as due to the inter-individual variability of drug metabolism, among others. Therefore, this work aims to raise awareness about possible pharmacological interactions with fruit juices. READ ARTICLE

Foods DOI: 10.3390/foods10010033

Authors: Zvonimir Petric, Irena Žuntar, Predrag Putnik and Danijela Bursać Kovačević

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The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer

Review providing a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized. READ ARTICLE

Pharmaceuticals (Basel) DOI: 10.3390/ph13120474

Authors: Valerio Gristina, Maria La Mantia, Federica Iacono, Antonio Galvano, Antonio Russo, Viviana Bazan

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MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development p..... READ ARTICLE

Journal of Hematology and Oncology DOI: 10.1186/s13045-020-01007-9

Authors: rnold Bolomsky, Meike Vogler, Murat Cem Köse, Caroline A. Heckman, Grégory Ehx, Heinz Ludwig, Jo Caers

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Overcoming TKI resistance in fusion-driven NSCLC: new generation inhibitors and rationale for combination strategies

Targeted therapies lead to acquired resistance through multiple mechanisms. The selective pressure of newer, more potent TKIs results in new resistance mechanisms. Article gives overview of strategies for overcoming resistance to TKIs targeting the common oncogenic gene fusions in NSCLC. READ ARTICLE

Translational Lung Cancer Research DOI: 10.21037/tlcr-2019-cnsclc-06

Authors: Alessandro Russo, Andrés F. Cardona, Christian Caglevic, Paolo Manca, Alejandro Ruiz-Patiño, Oscar Arrieta, Christian Rolfo

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The role of plasma genotyping in ALK- and ROS1-rearranged lung cancer

Review discusses technical aspects of plasma genotyping strategies and summarize findings from studies exploring plasma genotyping (including ctDNA analysis and profiling of nucleic acids contained in other plasma components) in two rearrangement-driven NSCLC subsets (ALK-rearranged and ROS1-rearranged). READ ARTICLE

Translational Lung Cancer Research DOI: 10.21037/tlcr-2019-cnsclc-09

Authors: Dagogo-Jack I, Ritterhouse LL.

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Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, commonly
defined by genetic alterations in oncogenic drivers. Targeted therapies
have transformed the management of oncogene-driven lung cancers, with
targeted agents now approved in the United States for 7 distinct
molecular alterations. Nonetheless, acquired resistance remains an
ongoing challenge, underscoring the need for alternative therapeutic
approaches. Immune checkpoint inhibitors targeting the programmed cell
death 1 (PD-1) axis have emerged as important therapies in the
management of advanced NSCLC, but the role of these agents in patients
with oncogenic driver mutations remains unclear. Here, we focus on
epidermal growth factor receptor-mutant and anaplastic lymphoma
kinase-rearranged NSCLC as paradigms to explore the role of immune
checkpoint inhibitors in oncogene-driven NSCLC. We provide an overview
of the clinical data examining programmed death ligand 1 (PD-L1)
inhibitor monotherapy, PD-(L)1 inhibitors, and tyrosine kinase inhibitor
combinations, as well as combinations of PD-(L)1 inhibitors and
chemotherapy. READ ARTICLE

Cancer Journal DOI:10.1097/PPO.0000000000000491

Authors: Gavralidis A, Gainor JF

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What Is the Standard First-Line Treatment for Advanced Non-Small Cell Lung Cancer?

The initial treatment regimens for advanced non-small cell lung cancer (NSCLC) have drastically evolved over the last 15 years with the rapid development of improved genomic sequencing technologies and the emergence of immune checkpoint inhibitors. Highly active oral kinase inhibitors are now approved for several molecularly defined subsets of NSCLC, including those harboring alterations in the EGFR, ALK, ROS1, BRAF, MET, RET, and NTRK genes, although acquired resistance to these targeted therapies remains a significant clinical challenge. In lung cancers lacking targetable mutations, programmed death 1/programmed death ligand 1 immune checkpoint inhibitors, used alone or in combination with cytotoxic T-lymphocyte-associated protein 4 inhibitors and/or cytotoxic chemotherapy, have led to meaningful improvements in overall survival. With many therapeutic options available to patients, here we review the recommended frontline treatment regimens for advanced NSCLC with and without targetable genomic drivers. READ ARTICLE

Cancer (Journal) DOI: 10.1097/PPO.0000000000000489

Authors: Ricciuti B, Awad MM.

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Functional coding/non-coding variants in EGFR, ROS1 and ALK genes and their role in liquid biopsy as a personalized therapy

Personalized medicine holds promise to tailor the treatment options for patients’ unique genetic make-up, behavioral and environmental background. Liquid biopsy is non-invasive technique and precise diagnosis and treatment approach. Significantly, NGS technologies have revolutionized the genomic medicine by novel identifying SNPs, indel mutations in both coding and non-coding regions and also a promising technology to accelerate the early detection and finding new biomarkers for diagnosis and treatment. The number of the bioinformatics tools have been rapidly increasing with the aim of learning more about the detected mutations either they have a pathogenic role or not. EGFR, ROS1 and ALK genes are members of the RTK family. Until now, mutations within these genes have been associated with many cancers and involved in resistance formation to TKIs. This review article summarized the findings about the mostly investigated variations in EGFR, ROS1 and ALK genes and their potential role in..... READ ARTICLE

Critical Reviews in Oncology/Hematology DOI:10.1016/j.critrevonc.2020.103113

Authors: Mahmut Cerkez Ergoren, Havva Cobanogulları, Sehime Gulsun Temel, Gamze Mocan

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PCN68 An Incremental Effectiveness Analysis of Lorlatinib for the Treatment of ALK-Positive Advanced Non-Small Cell Lung Cancer that has Progressed after Another ALK...

Objectives To evaluate the incremental effectiveness of anaplastic lymphoma kinase (ALK) inhibitor lorlatinib compared to platinum-based chemotherapy (PBC) for adult patients with ALK-positive advanced non-small cell lung cancer (NSCLC) whose disease progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy or after crizotinib and at least one other ALK TKI in the Portuguese setting. Conclusions Lorlatinib results in increased life expectancy and quality-adjusted life expectancy compared with PBC in previously treated adult patients with ALK-positive NSCLC in the Portuguese setting. READ ARTICLE

Value in Health DOI:10.1016/j.jval.2020.08.205

Authors: R. Guerreiro, A.T. Paquete, L. Iadeluca, C. Almond, F. Albuquerque de Almeida, M. Inês, J. Costa, M. Borges, L. Silva Miguel,

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PCN6 Matching-Adjusted Indirect Treatment Comparisons (MAIC) of the Effect of Lorlatinib Versus Chemotherapy on Overall Survival (OS) and Progression-Free Survival (PFS) for Patients with ...

Objectives: To compare the relative efficacy of the ALK-tyrosine kinase inhibitor (TKI) lorlatinib, investigated in the single-arm Phase I/II trial B7461001 as a second-line or later treatment for patients with advanced ALK-positive NSCLC, to chemotherapy, a key comparator within this indication. Conclusions Lorlatinib consistently demonstrated a significant improvement in the outcomes of both PFS and OS when compared with chemotherapy, although the evidence base is limited. READ ARTICLE

Value in Health DOI:10.1016/j.jval.2020.08.143

Authors: S. Smith, F. Albuquerque de Almeida, M. Inês, L. Iadeluca, M. Cooper

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A Novel Sequentially Evolved EML4-ALK Variant 3 G1202R/S1206Y Double Mutation In Cis Confers Resistance to Lorlatinib: A Brief Report and Literature Review

Lorlatinib is a third-generation ALK inhibitor that can overcome the largest number of acquired ALK resistance mutations, including the solvent-front mutation G1202R. Here, we report, for the first time, a novel, sequentially-evolved EML4-ALK variant 3 G1202R/S1206Y double mutation in cis detected in a patient with ALK-positive NSCLC after disease progression on sequential crizotinib, alectinib, and then lorlatinib. Three-dimensional computer modeling of this double mutation and other G1202R-based double mutations with lorlatinib (ALK G1202R/L1196M, ALK G1202R/F1174C, ALK G1202R/l1198F, ALK G1202R/G1269A) were provided to reveal how these double mutations may confer resistance to lorlatinib through diverse steric hindrances in the ALK kinase domain. In addition, we performed a comprehensive literature review on published acquired double or triple ALK mutations that are resistant to lorlatinib from both patient samples and in vitro mutagenesis experiments. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtocrr.2020.100116

Authors: Viola W. Zhu, Misako Nagasaka, Russell Madison, Alexa B. Schrock, Jean Cui, Sai-Hong Ignatius Ou

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Beyond EGFR, ALK and ROS1: Current evidence and future perspectives on newly targetable oncogenic drivers in lung adenocarcinoma

Lung cancer is the leading cause of cancer death worldwide. In the past decade EGFR, ALK and ROS1 TKIs lead to an unprecedented survival improvement of oncogene-addicted NSCLC patients, with better toxicity profile compared to chemotherapy. In recent years the implementation of high-throughput sequencing platforms led to the identification of uncommon molecular alterations in oncogenic drivers, such as BRAF, MET, RET, HER2 and NTRK. Moreover, newly developed drugs have been found to be active against hard to target drivers, such as KRAS. Specific TKIs targeting these genomic alterations are currently in clinical development and showed impressive activity and survival improvement, leading to FDA-accelerated approval for some of them. However, virtually all patients develop resistance to TKIs by on-target or off-target mechanisms. Here we review the clinicopathological features, the emerging targeted therapies and mechanisms of resistance and strategies to overcome them of KRAS, BRAF, MET, RET, HER2 and NTRK-addicted advanced NSCLCs. READ ARTICLE

Critical Reviews in Oncology/Hematology DOI: 10.1016/j.critrevonc.2020.103119

Authors: Giuseppe Lamberti, Elisa Andrini, Monia Sisi, Alessandro RizzoaClaudia Parisi, Alessandro Di Federico, Francesco Gelsomino and Andrea Ardizzoni

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Treatment Optimization for Brain Metastasis from Anaplastic Lymphoma Kinase Rearrangement Non-Small-Cell Lung Cancer

Background: Brain metastasis is common in non-small-cell lung cancer (NSCLC) with driver gene mutations. Anaplastic lymphoma kinase (ALK) gene rearrangement is one of the common driver mutations in NSCLC. Tyrosine kinase inhibitor (TKI) has been the research hotspot at present. However, there are relatively few studies specified on the treatment of brain metastasis from ALK gene rearrangement NSCLC. The prognosis of these patients, the role of ALK-TKI, and the proper combination model of ALK-TKI with radiotherapy are worth further exploring. This review focuses on new data on the prognosis of ALK-TKI and the proper combination model of ALK-TKI with radiotherapy. Key Messages: Next-generation ALK-TKIs are now replacing crizotinib as first-line treatment in ALKi-naïve ALK rearrangement NSCLC patients with brain metastasis, and they alone might have a strong efficacy against intracranial tumors in crizotinib-refractory situations in which occasion radiotherapy might be omitted. SRS and W..... READ ARTICLE

Oncology Research and Treatment DOI:10.1159/000502755

Authors: Wang W., Sun X., Hui Z.

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Les réarrangements moléculaires : cibles thérapeutiques en cancérologie thoracique Fusion transcripts: Therapeutic targets in thoracic oncology

Five to ten percent of lung adenocarcinoma harbor chromosomal rearrangements affecting the ALK, ROS1, NTRK and RET genes. These rearrangements are associated with the production of fusion transcripts that lead to the synthesis of chimeric proteins with constitutive kinase activity. These abnormal proteins induce an oncogenic dependency that may be targeted by tyrosine kinase inhibitors. In this review, we will summarize the clinical and molecular epidemiology of chromosomal rearrangements affecting ALK, ROS1, NTRK and RET genes. We will describe the mechanisms of resistance to tyrosine kinase inhibitors that have been reported. We will present the molecular techniques that can be used to detect these rearrangements and the strategies set-up by the molecular oncology laboratories to diagnose these genetic alterations. READ ARTICLE

Bulletin du Cancer DOI:10.1016/j.bulcan.2020.05.008

Authors: Audrey Mansuet-Lupo, Simon Garinet, Diane Damotte, Marco Alifano, Hélène Blons, Marie Wislez, Karen Leroy

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Clinical Utility of Reflex Ordered Testing for Molecular Biomarkers in Lung Adenocarcinoma

Introduction: In order to standardize and expedite molecular biomarker testing, we implemented reflex ordered testing of targeted gene alterations in newly diagnosed lung adenocarcinomas within our hospital system... Conclusions: Reflex ordered testing of molecular biomarkers in lung adenocarcinoma led to significantly decreased TAT within our hospital system and higher detection rates of targeted gene alterations. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2020.05.007

Authors: Kartik Anand, Thuy L. Phung, Eric H. Bernicker, Philip T. Cagle, Randall J. Olsen, Jessica S. Thomas

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1301P Blood first assay screening trial (BFAST) in patients (pts) with 1L NSCLC: ALK+ cohort updated biomarker analyses

Clinical trial identification: NCT03178552. Background: BFAST (NCT03178552) is a global, multi-cohort study evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations in circulating tumour DNA and activity of targeted therapies/immunotherapy in pts with 1L advanced NSCLC. In the ALK+ cohort, investigator-assessed objective response rate (ORR) was 87.4% and 12-month progression-free survival (PFS) rate was 78.4% with alectinib. We present updated ALK+ cohort biomarker analyses (median follow-up: 18.2 months)... Conclusions: Molecular heterogeneity in ALK+ NSCLC may influence clinical efficacy of ALK inhibitors such as alectinib. Larger, more mature datasets are needed to identify and validate additional biomarkers predictive of limited benefit from ALK inhibitors. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2020.08.1615

Authors: S. M. Gadgeel, M. Yan, S. M. Paul, M. Mathisen, S. Mocci, Z. J. Assaf, R. Patel, E. S. Sokol, T. Mok, S. Peters, L. Paz-Ares, R. Dziadziuszko

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Analysis of multigene detection in patients with advanced lung adenocarcinoma using cytological specimens

Objective: To investigate the mutation status and clinical characteristics of multigene detection in advanced lung adenocarcinoma using cytological specimens... Conclusions: In the study, cytological specimens and biopsy samples have a very high coincidence rate of gene detection. EGFR, ALK and ROS1 mutations were the main driver mutations in patients with advanced lung adenocarcinoma. We speculate that EGFR and ALK are more prone to concomitant mutations respectively and the treatment of advanced lung adenocarcinoma patients with concomitant mutations deserves further study. The rate of KRAS, NRAS, BRAF, PIK3CA, RET and MET exon14 skipping mutation were low but may had a significant impact on the targeted therapy of patients with advanced lung adenocarcinoma. READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2020.153036

Authors: Yang Ma, Yun Du, Rui Wang, Xiaokun Ji, Juan Wu, Ying Liu, Xiao Guo, Yan Zhang

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Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients

Background: Kinase fusions are rare and poorly characterized in breast cancer (BC). We aimed to characterize kinase fusions within a large cohort of advanced BC... Results: Twenty-seven of 4854 (0.6%) patients harbored fusions: 11 FGFR (five FGFR2, three FGFR3, three FGFR1), five BRAF, four NTRK1, two RET, two ROS1, one ALK, one ERBB2, and one MET... Conclusion: Kinase fusions in BC are extremely rare, and appear to be enriched in hormone-resistant, metastatic carcinomas and mutually exclusive with ESR1 mutations. The present study expands the spectrum of genetic alterations activating mitogen-activated protein kinase (MAPK) signaling that can substitute for ESR1 mutations in this setting. Molecular testing at progression after endocrine therapy should include fusion testing, particularly in the absence of ESR1 hotspot alterations, in an effort to identify additional therapeutic options which may provide substantial clinical benefit. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2020.04.008

Authors: D. S. Ross, B. Liu, A. M. Schram, P. Razavi, S. M. Lagana, Y. Zhang, M. Scaltriti, J. F. Bromberg, M. Ladanyi, D. M. Hyman, A. Drilon, A. Zehir, R. Benayed, S. Chandarlapaty, J. F. Hechtman

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Optimal Care for Patients with Anaplastic Lymphoma Kinase (ALK)–Positive Non–Small Cell Lung Cancer: A Review on the Role and Utility of ALK Inhibitors

The treatment of advanced non–small-cell lung cancer (NSCLC) has undergone a paradigm shift in the last decade. Molecular characterization of the disease has led to the rapid development of personalized medicine and swift delivery of targeted therapies to patients. The discovery of the anaplastic lymphoma kinase (ALK) gene in patients with NSCLC has resulted in rapid bench–bedside transition of several active drugs, with several others currently in clinical trials. After the first-generation ALK inhibitor crizotinib, next-generation ALK inhibitors have entered clinical applications for ALK-rearranged NSCLC. Ceritinib, alectinib, and brigatinib have all received approval for ALK-positive patients who have failed prior crizotinib, as well as first-line therapy in treatment-naïve patients based on favorable efficacy. Most recently, lorlatinib, a potent, newer-generation ALK inhibitor, has been approved as second- or third-line treatment. These advances have led to better patient outcomes,..... READ ARTICLE

Cancer Management and Research DOI:10.2147/CMAR.S260274

Authors: Abhay Singh, Hongbin Chen

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